Although patients with aggressive non-Hodgkins's lymphoma (NHL) can be cured with combination chemotherapy, over 50% of these patients still die of their disease. Despite the inclusion of additional active agents and modification of drug doses and schedules, we have not made a significant impact on the upfront therapy of this curable disease in 15 years. Although we have developed clinical prognostic factor models that help us distinguish curable patients from ones who are unlikely to benefit from current regimens, these models are imprecise. We believe the imprecision is due to the fact that the clinical factors are only surrogate markers for the cellular and molecular heterogeneity of this disease. To further characterize cellular and molecular heterogeneity in aggressive NHL, we will identify and specifically treat patients with high-risk aggressive NHL, making use of newly defined clinical and molecular markers and experimental treatment regimens (Specific Aim 1). We will also define additional cellular featrues that reflect the biological heterogeneity of aggressive NHL, focusing on specific aspects of tumor cell trafficking (CD44 isoform expression) and tumor cell immunogenicity (pHTCL and pCTCL) (Specific Aim 2). Finally, we will identify novel molecular markers of the biological heterogenicity of aggressive NHL using "high-" and "low-risk" patient tumor samples and the recently described technique of differential display (Specific Aim 3). The success of this project is highly dependent upon the coordinated efforts of the indicated investigators, program collaborators, expert clinicians and core personnel.